This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Chronic orofacial (OFP) pain is common worldwide, adversely influences quality of life, and imposes substantial costs on the healthcare system. It has been found that inflammatory and neuropathic components can contribute to the maintenance of these pain conditions mediated by sensory neurons housed within the trigeminal (V) brain stem sensory nuclear complex. Direct gene transfer to sensory nerves at these sites offers the ability to selectively interrupt nociceptive neurotransmission or interfere with underlying processes contributing to the maintenance of persistent pain. In this proposal, we describe studies that use innovative technology (i.e., viral vector-based gene transfer) for the treatment of chronic OFP pain. Our goal is to alleviate inflammatory (Aim 1) and neuropathic (Aim 2) OFP pain in a safe (Aim 3) and effective manner using recombinant herpes simplex virus (HSV)-based vectors that are naturally suited to provide delivery of human genes to the trigeminal ganglia (TG). Our overall hypothesis is that HSV based gene therapy can be used effectively and safely to alleviate chronic orofacial pain. To address this hypothesis we will use recombinant replication-incompetent HSV vectors engineered to produce human opioid peptides or glutamic acid decarboxylase (GAD) in TG neurons for the relief of chronic pain in the orofacial region. The overall hypothesis of this project is that HSV based gene therapy can be used effectively and safely to alleviate orofacial pain. Our Specific Aims are: 1. Test the hypothesis that expression of endomorphin in rat TGs results in more effective abrogation of inflammatory orofacial pain than expression of enkephalin and glutamic acid decarboxylase. 2. Test the hypothesis that expression of glutamic acid decarboxylase in rat TGs results in more effective abrogation of neuropathic orofacial pain than expression of enkephalin and endomorphin.